Cancer is an emerging public health concern in sub-Saharan Africa. In Botswana, the most prevalent cancers are HIV related. The symptom burden that results from cancer and HIV infection is associated with poorer quality of life (QOL). This cross-sectional study examined the relationship between symptom burden and QOL in adult patients with cancer with or without HIV in Botswana. No statistically significant differences were observed in symptom burden and QOL between study participants with or without HIV. Symptom burden was the strongest predictor of QOL in the cohort.